Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity.
Patients with Chronic Chagas' Heart Disease possess high levels of antibodies against the carboxyl-terminal end of the ribosomal P2ß protein of Trypanosoma cruzi (TcP2ß). These antibodies, as well as the murine monoclonal antibody (mAb) 17.2, recognize the last 13 amino acids of TcP2ß (called t...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2011-11-01
|
Series: | PLoS Neglected Tropical Diseases |
Online Access: | http://europepmc.org/articles/PMC3206007?pdf=render |
id |
doaj-6e608724de6844cdae7c66dd5579fbb0 |
---|---|
record_format |
Article |
spelling |
doaj-6e608724de6844cdae7c66dd5579fbb02020-11-25T01:43:05ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352011-11-01511e137510.1371/journal.pntd.0001375Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity.Juan Carlos PizarroGinette BoulotGraham A BentleyKarina A GómezJohan HoebekeMireille HontebeyrieMariano J LevinCristian R SmulskiPatients with Chronic Chagas' Heart Disease possess high levels of antibodies against the carboxyl-terminal end of the ribosomal P2ß protein of Trypanosoma cruzi (TcP2ß). These antibodies, as well as the murine monoclonal antibody (mAb) 17.2, recognize the last 13 amino acids of TcP2ß (called the R13 epitope: EEEDDDMGFGLFD) and are able to cross-react with, and stimulate, the ß1 adrenergic receptor (ß1-AR). Indeed, the mAb 17.2 was able to specifically detect human β1-AR, stably transfected into HEK cells, by flow cytometry and to induce repolarisation abnormalities and first degree atrioventricular conduction block after passive transfer to naïve mice. To study the structural basis of this cross-reactivity, we determined the crystal structure of the Fab region of the mAb 17.2 alone at 2.31 Å resolution and in complex with the R13 peptide at 1.89 Å resolution. We identified as key contact residues on R13 peptide Glu3, Asp6 and Phe9 as was previously shown by alanine scanning. Additionally, we generated a model of human β1-AR to elucidate the interaction with anti-R13 antibodies. These data provide an understanding of the molecular basis of cross-reactive antibodies induced by chronic infection with Trypanosoma cruzi.http://europepmc.org/articles/PMC3206007?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Juan Carlos Pizarro Ginette Boulot Graham A Bentley Karina A Gómez Johan Hoebeke Mireille Hontebeyrie Mariano J Levin Cristian R Smulski |
spellingShingle |
Juan Carlos Pizarro Ginette Boulot Graham A Bentley Karina A Gómez Johan Hoebeke Mireille Hontebeyrie Mariano J Levin Cristian R Smulski Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity. PLoS Neglected Tropical Diseases |
author_facet |
Juan Carlos Pizarro Ginette Boulot Graham A Bentley Karina A Gómez Johan Hoebeke Mireille Hontebeyrie Mariano J Levin Cristian R Smulski |
author_sort |
Juan Carlos Pizarro |
title |
Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity. |
title_short |
Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity. |
title_full |
Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity. |
title_fullStr |
Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity. |
title_full_unstemmed |
Crystal structure of the complex mAb 17.2 and the C-terminal region of Trypanosoma cruzi P2β protein: implications in cross-reactivity. |
title_sort |
crystal structure of the complex mab 17.2 and the c-terminal region of trypanosoma cruzi p2β protein: implications in cross-reactivity. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Neglected Tropical Diseases |
issn |
1935-2727 1935-2735 |
publishDate |
2011-11-01 |
description |
Patients with Chronic Chagas' Heart Disease possess high levels of antibodies against the carboxyl-terminal end of the ribosomal P2ß protein of Trypanosoma cruzi (TcP2ß). These antibodies, as well as the murine monoclonal antibody (mAb) 17.2, recognize the last 13 amino acids of TcP2ß (called the R13 epitope: EEEDDDMGFGLFD) and are able to cross-react with, and stimulate, the ß1 adrenergic receptor (ß1-AR). Indeed, the mAb 17.2 was able to specifically detect human β1-AR, stably transfected into HEK cells, by flow cytometry and to induce repolarisation abnormalities and first degree atrioventricular conduction block after passive transfer to naïve mice. To study the structural basis of this cross-reactivity, we determined the crystal structure of the Fab region of the mAb 17.2 alone at 2.31 Å resolution and in complex with the R13 peptide at 1.89 Å resolution. We identified as key contact residues on R13 peptide Glu3, Asp6 and Phe9 as was previously shown by alanine scanning. Additionally, we generated a model of human β1-AR to elucidate the interaction with anti-R13 antibodies. These data provide an understanding of the molecular basis of cross-reactive antibodies induced by chronic infection with Trypanosoma cruzi. |
url |
http://europepmc.org/articles/PMC3206007?pdf=render |
work_keys_str_mv |
AT juancarlospizarro crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity AT ginetteboulot crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity AT grahamabentley crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity AT karinaagomez crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity AT johanhoebeke crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity AT mireillehontebeyrie crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity AT marianojlevin crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity AT cristianrsmulski crystalstructureofthecomplexmab172andthecterminalregionoftrypanosomacruzip2bproteinimplicationsincrossreactivity |
_version_ |
1725033428565360640 |